Several publications and patent documents are cited throughout the specification in order to describe the state of the art to which this invention pertains. Each of these citations is incorporated herein by reference as though set forth in full.
Regulatory RNAs play important roles in the control of gene expression in eukaryotic cells [1; 2]. Regulatory BC RNAs are translational repressors that have been implicated in the regulation of protein synthesis in mammalian nerve cells [3; 4; 5]. BCRNAs are small RNAs (150-200 nt, i.e. distinct from miRNAs) that function by interacting with components of the eukaryotic translational machinery [3; 4; 5]. Specifically, primate BC200 RNA and rodent BC1 RNA target the helicase activity of eukaryotic initiation factor 4A (eIF4A), an abundant canonical translation factor that is required for efficient initiation of mRNAs by unwinding higher-order structure content in their 5′ untranslated regions (UTRs) [5]. BC RNAs are not typically expressed in somatic mammalian cell types other than neurons. However, in a notable exception to this neuronal expression specificity, BC200 RNA was found expressed at high levels in human invasive breast carcinoma cells [6; 7]. In contrast, BC200 RNA was not detected in normal human breast epithelial cells or in benign tumors of the breast. The combined data suggested that regulatory BC200 RNA is recruited by invasive or pre-invasive breast carcinoma cells, thus promoting deregulation of cellular translational control [7].
Breast cancer remains a leading cause of death from malignancies in women, despite the fact that a combination of factors, including early detection (e.g. mammography) and improved therapeutic intervention (resection, adjuvant therapy), has in recent years resulted in a decrease of breast cancer mortality in the US [8]. But mammograms suffer from variable and significant false negative rates [9; 10; 11], and therapeutic intervention has been hampered by the lack of indicators, molecular and otherwise, that would aide physicians and patients in breast cancer treatment decisions. In particular, any improvement in our ability to predict treatment outcome, and to prognosticate tumor progression and recurrences, would have immediate clinical utility.